Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2‑Chloro-5-(1-(tetrahydro‑2H‑pyran-2-yl)‑1H‑pyrazol-5-yl)aniline

A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)­aniline (1), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling between in situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline (3) catalyzed by Pd­(Xantphos)­Cl2 enabled the construction of the key aryl–heteroaryl bond. A scalable first-generation process was developed that delivered 1 in multikilogram quantities. Building upon knowledge from the initial process, a more efficient workup and isolation procedure was developed that controlled levels of residual Pd and Zn to consistent levels that were acceptable for downstream processing. The high-yielding optimized process offers streamlined metals remediation, a 30% reduction in the number of unit operations, and a 34% reduction in process mass intensity (PMI) compared to the initial process.